Calcium phosphate bone replacement materials and methods of use thereof

ABSTRACT

Methods of making porous calcium phosphate bone replacement materials are discussed.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application SerialNo.: 60/342,622, filed Dec. 21, 2001, entitled “Calcium Phosphate BoneReplacement Materials and Methods of Use Thereof.” The entire contentsof the aforementioned application are hereby incorporated herein byreference in its entirety.

BACKGROUND

Trauma, pathological degeneration, or congenital deformity may result inthe need for surgical reconstruction or replacement of bone tissue.Reconstructive surgery is based upon the principle of replacingdefective bone tissue with viable, functioning alternatives. In skeletalapplications, surgeons have historically used bone grafts. The two maintypes of bone grafts currently used are autografts and allografts. Anautograft is a section of bone taken from the patient's own body, whilean allograft is taken from a cadaver. This method of grafting providesthe defect site with structural stability and natural osteogenicbehavior. However, both types of grafts are limited by certainuncontrollable factors. For autografts, the key limitation is donor sitemorbidity where the remaining tissue at the harvest site is damaged byremoval of the graft. Other considerations include the limited amount ofbone available for harvesting, and unpredictable resorptioncharacteristics of the graft. The main limitation of allografts has beenthe immunologic response to the foreign tissue of the graft. The tissueis often rejected by the body and is subject to the inflammatoryresponse. Allografts are also capable of transmitting disease. Althougha thorough screening process eliminates most of the disease carryingtissue, this method is not 100% effective.

Conventional orthopedic implants such as screws, plates, pins and rodsserve as loadbearing replacements for damaged bone and are usuallycomposed of a metal or alloy. Although these implants are capable ofproviding rigid fixation and stabilization of the bone, they causeimproper bone remodeling of the implant site due to the large differencein the modulus between bone and metal.

These limitations have initiated the search for a dependable syntheticbone graft substitute. However, in order for an implant to be used as areplacement for bone, it must be capable of both osteointegration andosteoconduction. Osteointegration refers to direct chemical bonding of abiomaterial to the surface of bone without an intervening layer offibrous tissue. This bonding is referred to as the implant-boneinterface. A primary problem with skeletal implants is mobility. Motionof the implant not only limits its function, but also predisposes theimplant site to infection and bone resorption. With a strongimplant-bone interface, however, mobility is eliminated, thus allowingfor proper healing to occur. Osteoconduction refers to the ability of abiomaterial to sustain cell growth and proliferation over its surfacewhile maintaining the cellular phenotype. For osteoblasts, the phenotypeincludes mineralization, collagen production, and protein synthesis.Normal osteoblast function is particularly important for porous implantsthat require bone ingrowth for proper strength and adequate surface areafor bone bonding.

Calcium phosphate-based materials have been investigated for use as bonereplacement materials. Most calcium phosphate biomaterials arepolycrystalline ceramics characterized by a high biocompatibility, theability to undergo osteointegration, and varying degrees ofresorbability. Implants made from these materials can be in either aporous or non-porous form. Examples of commercially available calciumphosphate materials include Interpore 200 and Interpore 500. Surgicalmodels using previously developed porous calcium phosphate-based implantmaterials, however, have shown that porous implants heal more slowlythan both autografts and empty defects (Nery et al. J. Periodotol. 197546:328; Levin et al. J. Biomed. Mat. Res. 1975 9:183). Studies on tissueingrowth in non-resorbable implants have also shown that failure oftissue to completely fill the implant can lead to infection (Feenstra,L. and De Groot, K. “Medical use of calcium phosphate ceramics” InBioceramics of Calcium Phosphate, De Groot, K. Ed., CRC Press, BocaRaton, Fla., 1983, pp 131–141; Feldman, D. and Esteridge, T.Transactions 2nd World Congress Biomaterials Society, 10th AnnualMeeting, 1984, p 37).

Implants synthesized from the calcium phosphate-based material,hydroxyapatite (HA), the major mineral constituent of bone, arecommercially available in a porous and non-porous form. Synthetic HAimplants have excellent biocompatibility. Blocks of dense HA are notuseful in reconstructive surgery because they are difficult to shape anddo not permit tissue ingrowth. However, in a non-porous, particulateform, HA has been used successfully in both composite (Collagraft) andcement (Hapset) forms (Chow et al. Mater. Res. Soc. Symp. Proc. 1993179:3–24; Cornell, C. N. Tech. Orthop. 1992 7:55). Due to its fragilityand lack of compliance, porous HA have been largely limited to dentaland maxillofacial surgery.

SUMMARY OF THE INVENTION

In one embodiment, the invention pertains, at least in part, to a methodof producing a porous calcium phosphate material. The method includesforming a mixture of calcium ions and phosphate ions having a calcium tophosphorus ratio of 0.1 to 1.67, heating the mixture to an appropriatereaction temperature, and cooling the reaction mixture.

In another embodiment, the invention pertains, at least in part, to amethod of producing a porous calcium phosphate material. The methodincludes forming a mixture of calcium ions and phosphate ions, having acalcium to phosphorus ratio of 0.1 to 1.67, adding a gas-generatingmaterial to the mixture, heating said mixture an appropriatetemperature, and cooling the mixture. Preferably, the porous calciumphosphate material produced has interconnected pores.

In another embodiment, the invention also pertains to another method ofproducing a porous calcium phosphate material. The method includesmixing a gas-generating material and a calcium phosphate ceramicprecursor, heating the mixture to below the sintering temperature togenerate a gas, and sintering the calcium phosphate ceramic precursorsto make solid ceramic materials.

In another embodiment, the invention pertains to yet another method ofproducing a calcium phosphate material. This method includes 1 subliminga solid chemical in a reactive calcium phosphate mixture or calciumphosphate ceramic precursor, and before undergoing the chemical reactionor sintering the calcium phosphate ceramic precursor.

The invention also pertains, at least in part, to surgical implantswhich contain a calcium phosphate material produced by the methods ofthe invention.

In another, embodiment, the invention also pertains to synthetic calciumphosphate material produced by the methods of the invention. In afurther embodiment, the calcium phosphate material generated by themethods of the invention is biodegradable.

In a further embodiment, the invention also pertains to a method oftreating of bone disorder in a subject. The method includes applying acalcium phosphate material of the invention to a bone of said subject,such that the bone disorder of said subject is treated.

In another embodiment, the invention also pertains to a calciumphosphate material, comprising the calcium salt of:

wherein n is an integer between 10 and 1,000,000.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 a is a SEM image of the control calcium phosphate material at26.4 magnification.

FIG. 1 b is a SEM image of the calcium phosphate material with using 15%ammonium bicarbonate (particle size greater than 425 μm) at20×magnification.

FIG. 1 c is an image of the calcium phosphate material with 20% ammoniumbicarbonate (particle size less than 106 μm) at a 26.4×magnification.

FIG. 1 d is a SEM image of the calcium phosphate material with 20%ammonium bicarbonate (particle size between 212–250 μm) at a26.4×magnification.

FIG. 1 e is a SEM image of the calcium phosphate material with 20%ammonium bicarbonate (particle size between 250 and 425 μm) at a26.4×magnification.

FIG. 1 f is a SEM image of the calcium phosphate material with 20%ammonium bicarbonate (particle size between 250 and 425 μm)at a50.5×magnification.

FIG. 1 g is a SEM image of the calcium phosphate material with 25%ammonium bicarbonate (particle size between 125 and 250) at a26.4×magnification.

FIG. 2 is a histogram which shows the frequency of pore diameters forcontrol calcium phosphate material (without gas-generating material),calcium phosphate made with 20% of a gas-generating material, andcalcium phosphate material made with 25% of a gas-generating material.

DETAILED DESCRIPTION OF THE INVENTION

A new synthetic calcium phosphate material has been developed. The size,shape and porosity can be both predetermined and controlled in thesynthetic process. Pore size and density are important in promotingtissue ingrowth. Both the nonporous and porous materials demonstratehigh flexural and compressive strength compared to the other availableceramics and are comparable to autologous bone. This material is a purecalcium phosphate devoid of contaminants such as silicates, zinc andalumina which may possibly retard osteogenesis.

In one embodiment, the invention pertains to a method of producingcalcium phosphate material. The method includes forming a mixture ofcalcium ions and phosphate ions having a calcium to phosphorus ratio of0.1 to 1.67, heating the mixture to an appropriate reaction temperature;and cooling the reaction mixture. The ratio of calcium to phosphate ionsis preferably selected such that the resulting material is able toperform its intended function. For convenience, the calcium to phosphateion ratio is abbreviated as the “Ca/P ratio.”

The term “calcium phosphate material” includes synthetic materialcomprised of calcium and phosphate ions and, advantageously,non-apatitic. Preferably, the material is synthesized by the methods ofthe invention and is suitable for its intended purpose, e.g., as a bonereplacement. The calcium phosphate material of the invention,advantageously, is porous. The pores may or may not be interconnected.

In a further embodiment, the Ca/P ration is about 0.20 to about 0.80,about 0.25 to about 0.75, about 0.30 to about 0.70, about 0.35 to about0.65, about 0.40 to about 0.60, about 0.40 to about 0.55, about 0.45 toabout 0.50, about 0.46 to about 0.50, about 0.47 to about 0.50, about0.475 to about 0.495, about 0.480 to about 0.490, or about 0.486.Advantageously the Ca/P ratio is selected on the basis of advantageousbiocompatibility and strength.

The calcium ions may be obtained from any source known in the art.Examples of sources of calcium ions that may be used include apatiticcalcium phosphates, non-apatitic calcium phosphates, calcium hydroxide,calcium oxide, calcium carbonate, calcium salts, calcium halide, calciummetal, and combinations thereof. In certain embodiments, the calcium ionsource is hydroxyapatite.

The phosphate ions may also be obtained from any source known in theart. Examples of sources of phosphate ions include, but are not limitedto, orthophosphoric acid, pyrophosphoric acids, condensed phosphates,phosphate of non-metal cations, metal phosphates, and combinationsthereof. In certain embodiments, the phosphate ion source isorthophosphoric acid.

In an embodiment, the invention pertains to a calcium phosphate materialof the invention having a 0.486 Ca/P ratio, synthesized fromhydroxyapatite and orthophosphoric acid.

The calcium phosphate material is, generally, a highly porous materialwith average pore sized ranging from, for example, about 5 μm to about1000 μm or greater. In an embodiment, the pore size averages about 50μm. In other embodiments, the pore size averages between about 20 μm andabout 200 μm, about 20 μm and about 190 μm, about 20 μm and about 180μm, about 20 μm and about 170 μm, about 20 μm and about 160 μm, about 20μm and about 150 μm, about 20 μm and about 140 μm, about 20 μm and about130 μm, about 20 μm and about 130 μm, about 20 μm and about 120 μm,about 20 μm and about 110 μm, about 20 μm and about 100 μm, about 20 μmand about 90 μm, about 20 μm and about 80 μm, about 20 μm and about 75μm, about 20 μm and about 70 μm, about 20 μm and about 65 μm, about 20μm and about 60 μm, about 25 μm and about 60 μm, about 30 μm and about60 μm, about 35 μm and about 60 μm, and about 40 μm and about 60 μm. Thestarting melting point and the molten temperature for this particularcalcium phosphate material of the invention is 885° C.

The term “appropriate reaction temperature” includes temperatures atwhich the phosphate and calcium ions can react and anneal, but are notmolten. In a further embodiment, the appropriate reaction temperature isabout 5° C. to 150° C. below the melting point of the mixture. Theappropriate reaction temperature may vary based on the Ca/P ratio andmay also be dependent on the calcium and phosphate ion sources.

In an embodiment, the mixture is preheated to an appropriate preheatingtemperature before reacting and annealing. Advantageously uponpreheating, the mixture of calcium and phosphate ions form manipulablepaste. The paste can then be shaped (e.g., by hand or by a mold) suchthat it can perform its intended function. Subsequent heating to atemperature 15° C. below its starting melting point will form a solid ofthe desired shape.

The term “appropriate preheating temperature” includes temperatures atwhich the phosphate is partially condensed and forms a manipulable pasteafter an appropriate length of time (e.g., about thirty minutes or atime sufficient to form a manipulable paste). In one embodiment, theappropriate preheating temperature is about 250° C.

In a further embodiment, the method also includes preheating the mixtureto 400° C. to 760° C. for at least 1 second at least once, prior to theheating the mixture to the appropriate reaction temperature. The mixturemay be preheated one, two, three or more times.

In another embodiment, the reaction mixture is compressed to a pressureof 10,000 psi. The reaction mixture may also be heated to 250° C. to400° C. for an appropriate time, e.g., at least thirty minutes.

The mixture may also be molded into a shape which is advantageous forits intended purpose. For example, the reaction mixture may be placedinto a mold prior to heating and pressed to a pressure of 100 psi to20,000 psi for at least 1 second.

The mixture may be subject to ultrasonic vibration during compression.Furthermore, an acid catalyst may be added to the reaction mixture. Theacid catalyst may be an inorganic or organic acid.

In a further embodiment, vacuum filtration of a salt solution andelectrophoresis, may be used to remove unreacted ions and the acidcatalyst from the porous solid calcium phosphate material after thereaction and annealing step.

The calcium phosphate mixtures may be heated by any appropriate methodknown in the art. Examples of heating mechanisms include electricfurnaces, radio frequency heating, laser radiation, and microwaveradiation. As used herein, the term “furnace” is used to refer to anydevice which is capable of heating a mixture of calcium and phosphateions to a temperature lower than the molten state where the reactantsmay react.

In a further embodiment, the mixture is placed on an inert supportingmaterial, such as boron nitride, such that reactions between the mixtureand the supporting material are prevented.

The invention also pertains to a surgical implant comprising a calciumphosphate material produced by the methods of the invention. Theinvention also pertains to a calcium phosphate material produced by themethods of the invention.

In one further embodiment, the calcium phosphate material is produced bymixing orthophosphoric acid and hydroxyapatite and rapidly heating themixture to 760° C., such that the mixture is dehydrated and partiallycondensed. The mixture is molded under high pressure and heated to anappropriate temperature (e.g., a temperature at which temperature thecomponents react but are not molten state, e.g., 15° C. below themixture's melting point).

In a further embodiment, the bulk density of the calcium phosphatematerial is manipulated by applying different pressure on the mixture inthe mold before heating. The pressure applied to the mixture can varyfrom 100 psi to 20,000 psi. The pressure on the material constitutes alow bulk density of about 1.00 gm/cm ³ and the 10,000 psi pressure makesa material of bulk density about 2.2 gm/cm³. In other embodiments, thecalcium phosphate material of the invention has a bulk density ofbetween about 1.0 gm/cm³ to about 2.5 gm/cm³, about 1.0 gm/cm³ to about2.2 gm/cm³, about 1.0 gm/cm³ to about 2.1 gm/cm³, about 1.0 gm/cm³ toabout 2.0 gm/cm³, about 1.0 gm/cm³ to about 1.9 gm/cm³, about 1.0 gm/cm³to about 1.8 gm/cm³, about 1.0 gm/cm³ to about 1.7 gm/cm³, about 1.0gm/cm³ to about 1.6 gm/cm³, about 1.0 gm/cm³ to about 1.5 gm/cm³, about1.1 gm/cm³ to about 2.2 gm/cm³, about 1.2 gm/cm³ to about 2.2 gm/cm³,and about 1.3 gm/cm³ to about 2.2 gm/cm³.

In another embodiment, acid catalysts are used to facilitate theformation of the calcium phosphate material. Acid catalysts may be fromorganic or inorganic (e.g., hydrochloric acid) sources. Acid catalystsfrom organic sources can later be oxidized into carbon dioxide andwater. Inorganic acids can be removed by water or by electrophoresis.The acid catalyst is added after the preheating stage (e.g., dehydrationand partially condensing stage) but before the heating to theappropriate reaction temperature (e.g., 15° C. below the molten state).In addition, this heating process to the appropriate reactiontemperature can be lengthened to make ensure that the organic acidcatalyst has been oxidized to carbon dioxide and water.

The unreacted soluble reactants or soluble components of the finalproduct can be removed by water or they can be more efficiently removedby electrophoresis. Soluble unreacted inorganic acid catalysts candissolve in water, although trapped acid in the highly porous materialmay diffuse out of the calcium phosphate material slowly. A moreefficient way to remove the catalysts is through the use ofelectrophoresis which can actively remove the ions out of the material.Unreacted soluble reactants, or unstable final components such as, forexample, pyrophosphate, can also be pulled out of the material much moreefficiently with electrophoresis.

The calcium phosphate materials of this invention may comprise a varietyof crystalline and amorphous substances. Various types of analyses haveindicated that solid calcium phosphate materials include apatite calciumphosphates, mono and dibasic calcium phosphates, pyrophosphates,metaphostates, polymetaphosphates, and orthophosphate species.

For certain uses, the porous calcium phosphate material of the inventionhas several significant advantages over solid calcium phosphatematerials, such as sintered hydroxyapatite. For example, the porouscalcium phosphate material of the invention is more biodegradable thanthe sintered hydroxyapatite and is therefore more suitable as a bonesubstitute. The osteoclasts at the site of the transplantation activelydissolve the porous calcium phosphate material. The porous calciumphosphate material is replaced by the real bone (deposited by theosteoblasts), while undergoing biodegradation. Advantageously, thedegradation rate of the porous calcium phosphate material is compatiblewith the rate of regeneration, such that the replacement does not loseits function before total degradation. In addition, the highlyinterconnected porosity advantageously allows for the penetration of theosteoclasts and osteoblasts into the porous calcium phosphate materialof the invention, such that the material eventually becomes living bone.Examples of porous calcium phosphate material with interconnected poresare shown in FIGS. 1 b–1 g.

In an embodiment, the porous calcium phosphate material of the inventionis produced by mixing orthophosphoric acid and hydroxyapatite. Themixture is then dehydrated and partial condensed by rapid heating to anappropriate temperature for an appropriate length of time (e.g., atemperature of about 760° C. for 30 seconds) once or repeatedly.

In another embodiment, the invention pertains to method of producing aporous calcium phosphate material. The method includes forming a mixtureof calcium ions and phosphate ions, having a calcium to phosphorus ratioof 0.1 to 1.67, adding a gas-generating material to the mixture, heatingthe mixture an appropriate reaction temperature, and cooling the mixturesuch that a solid, porous calcium phosphate material is produced.Preferably, the porous calcium phosphate material produced hasinterconnected pores. In a further embodiment, the appropriate reactiontemperature is about 5° C. to 150° C. below the melting point of themixture

To create porosity, gas-generating material may be incorporated into themixture of calcium and phosphate ions. The pore size of the calciumphosphate material may be determined by the size of the granules of thegas-generating material. For example, to generate a calcium phosphatematerial with pore sizes between about 250 μm and about 400 μm, the sizeof the granules of gas-generating material should also be between about250 μm and about 400 μm.

The term “gas-generating material” includes materials that generate gaswhen subjected temperatures below the appropriate reaction temperatureand/or at reduced pressures. Examples of gases that may be generated bythe gas-generating material include, but not limited to ammonia, water,hydrogen, or carbon dioxide.

In a further embodiment, the gas-generating material generates ammonia.Examples of sources of ammonia include, but are not limited to, ammoniumcarbonate, ammonium bicarbonate, ammonium acetate, ammonium hydroxide,ammonium nitrates, ammonium sulfates, ammonium hydrogenphosphate,ammonium dihydrogeuphosphate, ammonium fluorophosphates, ammioniumcitrate, ammonium hydrogencitrate, ammonium hydrogen difluoride,ammonium hydrogen oxalate hemihydrate, ammonium halides, ammonium salts,ammonia anhydride, ammonia solutions, and combinations thereof.

In another further embodiment, the gas-generating material is generatescarbon dioxide. Examples of sources of carbon dioxide include, but arenot limited to, ammonium carbonate, ammonium bicarbonate, metalcarbonates, non-metal carbonates and mixtures thereof.

For example, 15% by weight of the selected ammonium bicarbonate is mixedwith the mixture of calcium and phosphate ions. The mixture is thenmolded and placed in an electric furnace. Ammonium bicarbonate starts todecompose at roughly 60° C. The heating rate is carefully controlled,such that the decomposition of ammonium bicarbonate does not occur toovigorously and create cracks in the calcium phosphate material. Forexample, the heating rate may be about 0.5° C./minute and thetemperature may be held at 250° C. for 12 hours. This period of timeallows for the decomposition of ammonium bicarbonate before the highertemperature reactions of the calcium phosphate species.

FIGS. 1 a–1 g show calcium phosphate materials made with no, 15%, 20%,and 25% ammonium bicarbonate gas-generating materials (by weight, beforethe ammonium bicarbonate decomposed). FIG. 1 a shows the control calciumphosphate material. FIG. 1 b shows the calcium phosphate material using15% ammonium bicarbonate with a particle size greater than 425 μm. FIG.1 c shows a calcium phosphate material made with 20% ammoniumbicarbonate, with a particle size of less than 106 μm. FIG. 1 d shows acalcium phosphate material with 20% ammonium bicarbonate with a particlesize between 212–250 μm. FIG. 1 e shows a calcium phosphate materialmade with 20% ammonium bicarbonate, with a particle size between 250 and425 μm. FIG. 1 f shows a calcium phosphate material made with 20%ammonium bicarbonate with a particle size between 250 and 425 μm. FIG. 1g shows a calcium phosphate material made with 25% ammonium bicarbonatewith a particle size between 125 and 250.

FIG. 2 is a histogram which shows the frequency of pore diameters forcontrol calcium phosphate material (without gas-generating material),calcium phosphate made with 20% by weight of ammonium by carbonate (witha particle size of 125–250 μm), and calcium phosphate material made with25% by weight of ammonium carbonate with a particle size from about 106to about 125 μm.

The subsequent heating to a higher temperature affords the energy forthe reactive calcium phosphate species to react and a solid calciumphosphate ceramic material to be obtained after the heating process. Thecavities left behind by the decomposition of gas generating materialcreate interconnected pores within the calcium phosphate material.Mercury intrusion analysis shows the pore sizes have been significantlyenlarged compared with the native pore sizes produced by thecondensation reaction of the material. The percentage of porosity isalso more then that of the material without incorporation of the gasgenerating material.

In another embodiment, the mixture is placed into a mold and pressed toa pressure of 100 psi to 20,000 psi for at least 1 second before beingheated to the appropriate reaction temperature. In another embodiment,the mixture is subject to ultrasonic vibration bombardment while in themold.

In another embodiment, the invention also pertains to a method ofproducing a porous calcium phosphate material. The method includesmixing a gas-generating material and a calcium phosphate ceramicprecursor, heating the mixture to below the sintering temperature togenerate a gas, and sintering the calcium phosphate ceramic precursorsto make a solid material.

The term “calcium phosphate ceramic precursor” includes, for example,monocalcium phosphate hydrate (MCP), dicalcium phosphate hydrate (DCPD),dicalcium phosphate anhydrous (DCPA), octacalcium phosphate pentahydrate(OCP), tricalcium phosphate (TCP), alpha and beta from (hydroxyapatite),pentacalcium hydroxylphosphate (HAP), tetracalcium phosphate monoxide(TCPM), calcium pyrophosphate, calcium metaphospates, polycalciummetaphospates, and combinations thereof.

In another embodiment of this invention, a similar strategy can beapplied to make artificial porosity by using chemicals capable of beingsublimed at elevated temperature and/or reduced atmospheric pressure.For example, H₂O ice can be sublimed at sub-zero ° C. temperate undervacuum, which process has been referred as freeze drying. Granules ofselected sizes of ice can be mixed with mixture of reactive calciumphosphate species or calcium phosphate ceramic precursors, which ispre-chilled to sub-zero° C. The mixture can then be molded in a mod,which is also pre-chilled to sub-zero° C., the whole process would haveto be conducted in a cold room of 0° C. or below to prevent melting ofthe ice. After the mixture has been molded, the mixture block is placedin liquid nitrogen and then a flask connected to vacuum line. After 24hours of vacuum, the ice granules inside the block will be sublimed,leaving cavities inside the material without residues.

In an embodiment, the invention pertains to a method of producing aporous calcium phosphate material. This method comprises subliming achemical in a reactive calcium phosphate mixture precursor, and reactingthe reactive calcium phosphate mixture, to produce a porous calciumphosphate material.

In yet another embodiment, the invention also pertains at least in partto a method of producing a porous calcium phosphate material. The methodincludes subliming a chemical in one or more calcium phosphate ceramicprecursor and sintering the calcium phosphate precursor, to produce aporous calcium phosphate material.

In a further embodiment, the chemical is selected such that it iscapable of being sublimated at a temperature below 400° C. and/or at apressure of greater than 0.1 torr.

The invention also pertains, at least in part, to interconnected porouscalcium phosphate materials. The material may be generated by any methoddescribed herein. Advantageously, the material is capable ofosteointegration and osteoconduction. Osteointegration can be measuredas the percentage of the perimeter length of implant covered by bone, asdescribed in the Examples. In one embodiment, the amount ofosteointegration of the implant of the invention is about 5% or greater,about 10% or greater, about 11% or greater, about 12% or greater, about13% or greater, about 14% or greater, about 15% or greater, about 16% orgreater, about 17% or greater, about 18% or greater, about 19% orgreater, about 20% or greater, about 21% or greater, about 22% orgreater, about 23% or greater, about 24% or greater, about 25% orgreater, about 30% or greater, about 35% or greater, about 40% orgreater, about 45% or greater, about 50% or greater, about 55% orgreater, about 60% or greater, about 65% or greater, about 70% orgreater, about 75% or greater, about 80% or greater, about 85% orgreater, about 90% or greater, about 95% or greater, or about 100%.

In other embodiments, the calcium phosphate material of the inventionhas a compression strength of about 10,000 psi or greater, about 11,000psi or greater, about 12,000 psi or greater, about 13,000 psi orgreater, about 14,000 psi or greater, about 15,000 or greater, about16,000 psi or greater, about 17,000 psi or greater, about 18,000 psi orgreater, about 19,000 psi or greater, about 20,000 psi or greater, about21,000 psi or greater, about 22,000 psi or greater, about 23,000 psi orgreater, about 24,000 psi or greater, or about 25,000 psi or greater.

In other embodiments, the calcium phosphate material of the inventionhas a bulk density of between about 1.0 gm/cm³ to about 2.5 gm/cm³,about 1.0 gm/cm³ to about 2.2 gm/cm³, about 1.0 gm/cm³ to about 2.1gm/cm³, about 1.0 gm/cm³ to about 2.0 gm/cm³, about 1.0 gm/cm³ to about1.9 gm/cm³, about 1.0 gm/cm³ to about 1.8 gm/cm³, about 1.0 gm/cm³ toabout 1.7 gm/cm³, about 1.0 gm/cm³ to about 1.6 gm/cm³, about 1.0 gm/cm³to about 1.5 gm/cm³, about 1.1 gm/cm³ to about 2.2 gm/cm³, about 1.2gm/cm³ to about 2.2 gm/cm³, and about 1.3 gm/cm³ to about 2.2 gm/cm³.

In other embodiments, the calcium phosphate material has a porosity ofbetween about 20% and about 80%, about 25% and about 75%, about 30% andabout 70%, about 30% and about 65%, about 35% and about 65%, about 40%and about 65%, about 41% and about 65%, about 42% and about 65%, about43% and about 65%, about 44% and about 65%, about 45% and about 65%,about 46% and about 65%, about 47% and about 65%, about 48% and about65%, about 40% and about 64%, about 40% and about 63%, about 40% andabout 62%, about 40% and about 61%, about 40% and about 60%, about 40%and about 59%, and about 40% and about 58%.

The porosity can be measured by methods known to those of skill in theart, for example, by Mercury Intrusion Porosimetry (MIP). MercuryPorosimeters deliver fast, accurate pore structure data for a widevariety of materials. They are provide an automated analysis of porousmaterials with pore diameters ranging from 360 to 0.0055 μm and arecommericially available (Micromeritics, Norcross, Ga.).

In an embodiment, the reactive calcium phosphate mixture precursorcomprises calcium phosphates, non-apatitic calcium phosphates, calciumhydroxide, calcium oxide, calcium carbonate, calcium salts, calciumhalide and calcium metal, orthophosphoric acid, pyrophosphoric acids,condensed phosphates, phosphate or non-metal cations, metal phosphates,or mixtures thereof.

In an embodiment, the calcium phosphate material generated by themethods of the invention is biodegradable. In a further embodiment, thecalcium phosphate material of the invention further comprisesosteoinductive agents.

In a further embodiment, the calcium phosphate material comprises thecalcium salt of

wherein n is from about 10 to about 1,000,000. In a further embodiment,n is between 50 and 1,000,000.

The term “osteoinductive agents” includes agents known in the art toenhance bone formation. Examples of such agents include, but are notlimited to osteoprogenitor cells from bone morrow or bone morphogenicproteins.

In a further embodiment, the invention pertains to a method of treatinga bone disorder in a subject. The method includes applying a calciumphosphate material of the invention to a bone of said subject, andallowing the bone to heal, such that the bone disorder of said subjectis treated. Examples of bone disorders include fractures or other bonedefects which require bone replacement. Preferably, the subject is amammal, e.g., a sheep, dog, cat, horse, monkey, rabbit, mouse, bear, or,preferably, a human.

The methods of the present invention produce controllable porositywithin a biodegradable calcium phosphate material which is suitable forcertain applications where high porosity is favored. The higher porosityhas been reported to be beneficial for the infiltration of osteoclastsand osteoblasts into the ceramic material, and which facilities the turnover rate of the biodegradable ceramic that closely resembles the realbone.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the following claims. All patents,patent applications, and literature references cited herein are herebyexpressly incorporated by reference.

EXEMPLIFICATION OF THE INVENTION

The invention is further illustrated by the following examples whichshould not be construed as limiting.

EXAMPLE 1

30 gm of hydroxyapatite (from Mutter Chemical Company under the name oftricalcium phosphate, Ca₁₀(PO₄)₆(OH)₂) was added to 32.5 ml of 85%orthophosphoric acid in a porcelain bowl. The mixture was ground andheated at 760° C. for 30 seconds. This process was repeated twice. Themixture was cooled down and placed in a stainless mold. A hydraulicpress was used to compress the powder mixture in the mold to about10,000 psi for about 30 seconds and then removed from the mold. Thepressed mixture was then heated in an electric furnace on an inert boronnitride support. The heating rate was about +1.67° C./minute and thetemperature was held at 870° C. (e.g., 20° C. below 890° C., thebeginning of the molten state of the reacting mixture) for 12 hours.After the 12 hours' incubation, the calcium phosphate block was cooleddown slowly at the rate of −1.67° C./minute to room temperature.

Qualitative analysis of the block showed that the calcium phosphatematerial contained 19.65% calcium, 30.75% phosphorus, less than 0.1%nitrogen and less then 0.1% hydrogen. The infrared spectrum signatureindicated the existence of polymetaphospate in the solid and powderX-ray diffraction showed a mixture of other calcium phosphate species.

The bulk density of the material was about 1.46 cm/cm³. The apparentdensity was about 300 gm/cm³. The compression strength of the mixturewas about 20,000 psi. The porosity of the material was determined to bearound 50% with an average pore size of 50 μm, and the surface area isabout 0.019 m2/g. Vacuum infiltration with polymethacrylate andsubsequent removal of the calcium phosphate material with hydrofluoricacid created a negative representation of the porosity showing highlyinterconnectivity of the pores inside the material. The calcium tophosphorus ratio of this material was around 0.486.

EXAMPLE 2

30 gm of hydroxyapatite (from Mutchler Chemical, Ca₁₀(PO₄)₆(OH)₂) isadded to 32.5 ml of 85% orthophosphoric acid in a porcelain bowl. Themixture is ground and heated at 760° C. for 30 seconds and this processis repeated twice, before being cooled to room temperature. The mixtureis pressed under 10,000 psi for about 30 seconds. Then the mixture isheated in an electric furnace at a rate of 0.5° C./minute and thetemperature is held at 250° C. for 30 minutes. After the 30 minutes'incubation, the temperature is cooled down to room temperature. Theresulting mixture is a manipulable white-colored paste and which can beshaped with hand or placed in a mold. Then, the shaped paste is placedon an inert boron nitride surface in an electric furnace and thetemperature is raised at the rate of 1.67° C./minute to 870° C. (e.g.,20° C. below the beginning of the molten state of the reacting mixture).The temperature is then held at 870° C. for another 12 hours. At the endof the 870° C. incubation, the temperature is gradually reduced to roomtemperature at a rate of 1.67° C./minute.

Qualitative analysis of the block shows the calcium phosphate materialcontains 19.65% calcium, 30.75% phosphorus, less than 0.1% nitrogen andless then 0.1% hydrogen. Infrared spectrum signature indicates theexistence of polymetaphospate in the solid and powder X-ray diffractionalso shows a mixture of other calcium phosphate species in thecomposition.

The bulk density of this material is about 1.46 cm/cm³. The apparentdensity is about 3.00 gm/cm³. The compression strength of the mixture isabout 20,000 psi. Mercury intrusion shows the porosity of the materialis about 50%, with an average pore size 50 μm. The mercury intrusionalso shows that the surface area of the material is about 0.019 m²/g.Vacuum infiltration with polymethacrylate and subsequent removal of thecalcium phosphate material with hydrofluoric acid creates a negativerepresentation of the porosity showing highly interconnectivity of thepores inside the material. The calcium to phosphorus ratio of thismaterial is around 0.486.

EXAMPLE 3

Using the method described in Example 1, the pressure applied to themixture while being placed in a stainless mold is varied. The pressureapplied to the mold ranged from about 100 psi to 20,000 psi. The volumeof the resulting mixture varies corresponding to the applied pressure.After the subsequent heating in the furnace according to the sameprocedure described in Example 1, the bulk density of the pressuredmixture ranged from around 1.0 gm/cm³ to 2.2 gm/cm³.

EXAMPLE 4

30 gm of hydroxyapatite (from Mutchler Chemical Company under the nameof tricalcium phosphate, Ca₁₀(PO₄)₆(OH)₂) is added to 32.5 ml of 85%orthophosphoric acid in a porcelain bowl. The mixture is ground andheated at 760° C. for 30 seconds three times. The mixture is cooled downand 1 ml of 0.1M HCl is added to the mixture and the resulting mixtureis heated to 200° C. for five minutes. The resulting mixture is thenplaced in stainless mold. A hydraulic press is used to compress thepowder mixture in to the mold to about 10,000 psi for about 30 seconds.While pressing the mixture in the mold, a source of ultrasound, such asa ultrasound probe, may be applied on the stainless mold to help packingthe mixture inside the mold. The block of mixture is then removed fromthe mold. The pressed mixture is then heated in an electric furnacesitting on an inert boron nitride supporting material. The heating rateis about +1.67° C./minute and the temperature is held at 870° C. (e.g.,20° C. below 890° C., the beginning of the molten state of the reactingmixture) for 12 hours. After the 12 hours' incubation, the reactedcalcium phosphate block is cooled down slowly at the rate of −1.67°C./minute to room temperature. The acid is later removed byelectrophoresis described in Example 2.

EXAMPLE 5

With the same procedure described in either Example 1 or 3, after themixture has been heated under 870° C. for 12 hours, the mixture iscooled down and then placed in a vacuum flask, which is connected to avacuum line. The atmospheric pressure inside the flask is then reducedto 25 microns of mercury. 0.1 NaCl is then injected into the flask andthe material is totally submerged in the salt solution. The material isthen placed in a electrophoresis cell and 150 volts of voltage isapplied to the cell for 30 minutes. The material is then rinsed out in 1gallon of distilled water twice to remove the salt solution.

EXAMPLE 6

30 gm of hydroxyapatite (from Mutchler Chemical Co., Ca₁₀(PO₄)₆(OH)₂) isadded to 32.5 ml of 85% orthophosphoric acid in a porcelain bowl. Themixture is ground and heated at 760° C. for 30 seconds three times. Themixture is cooled down to room temperature. Particles of ammoniumbicarbonate are selected by sieves of pore sizes between 250 μm and 400μm. 1.5 parts by weight of the ammonium bicarbonate of selected particlesizes are mixed with 8.5 parts of the calcium phosphate mixture. Thismixture is pressed under 10,000 psi for 30 seconds and then heated in anelectric furnace. The heating rate is 0.5° C./minute and the temperatureis held at 250° C. for 12 hours. After the 12 hours' incubation thetemperature is raised at the rate of 1.67° C./minute of 870° C., 20° C.below the beginning of the molten state of the reacting mixture, and thetemperature stays at 870° C. for another 12 hours. At the end of 870° C.incubation, the temperature is gradually cooled down to room temperatureat the rate of 1.67° C./minute.

The bulk density of this material is about 1.3 gm/cm³. The apparentdensity is about 3.10 gm/cm³. The compression strength of the mixture isabout 11,000 psi. Mercury intrusion shows the its porosity is around58%, with average pore size 130 μm. Vacuum infiltration withpolymethacrylate and subsequent removal of the calcium phosphatematerial with hydrofluoric acid creates a negative representation of theporosity showing highly interconnectivity of the pores inside thematerial.

EXAMPLE 7

Using apatitic or non-apatitic calcium phosphate ceramic precursors tomake sintered form of solid material, these precursors can be mixed withcertain weight percentage of ammonium bicarbonate to create controlledporosity of desired sizes. The weight percentage can be varied accordingto the need. A 15 parts of selected pore sizes of solid ammoniumbicarbonate are mixed with 85 parts of alpha form tricalcium phosphate.The mixture is then pressed to make solid block. This block is thenplaced in an electric furnace and the temperate is raise slowly at therate of 0.5° C./minute to 250° C. and stays at 250° C. for 12 hours.After the 12 hours incubation, the temperature of the furnace is raisedto the sintering temperature of the alpha tricalcium phosphate.

EXAMPLE 8

To control porosity using chemicals capable of sublimation alpha formtricalcium phosphate, or other calcium phosphate ceramic precursors, canbe mixed with certain weight percentage of water ice at −20° C. tocreate controlled porosity of desired sizes. The alpha form tricalciumphosphate ceramic precursor needs to be pre-chilled in a cold room at 0°C. or below. The weight percentage can be varied according to the need.A 15 parts of selected pore sizes of solid water ice are mixed with 85parts of alpha form tricalcium phosphate. The mixture is then pressed ina pre-chilled mold below 0° C. to make solid block of the ceramicprecursor. This block is then placed in liquid nitrogen and subsequentlyin a container connected to a freeze drying apparatus. The temperatureis left to raise slowly as the vacuum at 200 micron Mercury is appliedto the material. After the 24 hours incubation, the dehydrated materialis then placed in an electric furnace and the temperature of the furnaceis raised to the sintering temperature of the furnace is raised to thesintering temperature of the alpha tricalciumn phosphate.

EXAMPLE 9

This example shows the use of the calcium phosphate material for spinalfusion in sheep.

Posterior spinal fusions are commonly performed for a wide variety ofdisorders including deformities, tumors and fractures. Large quantitiesof bone graft are often necessary. The standard procedure is to harvestsautologous bone graft from the iliac crest. This technique carries asignificant morbidity and complication rate, often involving a secondincision with the attendant risks of bleeding, infection and persistentdonor site pain. Furthermore, adequate graft may not be alwaysobtainable, especially following previous spinal operations, inosteoporotic patients with poor bone stock or treating patients withmetastatic tumor.

Allograft bone has been used as an alternative. Allografts may not be asreadily available, are not as effective as a posterior onlay substance,are costly to procure and have the potential for disease transmission.Due to these shortcomings, researchers have attempted to develop a bonegraft substitute. The ideal synthetic bone replacement would bemechanically comparable in strength to autologous bone, be easilyfashioned for implantation and possess the ability to be biologicallyincorporate. Implant materials composed of calcium phosphate areprobably the most biocompatible synthetic hard tissue implant materialspresently available. These ceramics are available as hydroxyapatite,tricalcium phosphates, or combinations of the two (porous, nonporousimplants or granular particles) Tricalcium phosphate is porous andrapidly degraded. It is also mechanically weaker than hydroxyapotite.Replamine form hydroxyapatite is formed by a hydrothermal exchangeprocess using coral (porites) as a porous calcium carbonate skeleton.Limitations include incorporate conversion of the carbonate, variablesizes and shapes of the original coral exo-skeleton and this material isalso structurally weak compared to biological bone.

MATERIALS AND METHODS

Implant Description

Highly porous calcium polyphosphate material with a calcium phosphateratio of 0.55 was fabricated from this animal study in match stickshapes. Pore diameter ranged up to 200 microns. The material wassterilized using radiation techniques.

OPERATIVE TECHNIQUE

12 conditioned adult male sheep were used in this example. After generalendotracheal anesthesia, each animal was placed prone on the operatingtable, prepped and draped in sterile fashion. Two midline longitudinalincisions were made. An incision between L1–2 was carried down to thespinous process. The midline spinous process and ligaments werepreserved and the dissection was carried laterally out to the tips ofthe transverse process, between L1 and L2. Decortication and facetectomywas accomplished using gauges and curettes. In similar fashion, aseparate incision was made at the L4–5 location and dissection carrieddown to the tips of the transverso process of L4 and 15 bilaterally andsimilar decortication and facetectomy accomplished. Cortical cancerousbone graft was harvested from both iliac crests in two separateincisions, using ostotomics and curettes. This autologous bone graft wasthen fashioned into small bony strips and bone graft was then implantedat the L1–2 level, bone graft being placed bilaterally in symmetricalfashion between the transverse processes of L1 and L2. A similarquantity and size of calcium phosphate bioceramic was placed between thetransverse processes of the L4–5 lumbar segment in similar fashion.Furthermore, calcium phosphate bioceramic match stick material was usedto fill the void created over the left iliac crest which was then closedin standard fashion with vinyl sutures in layers. The right iliac crestdonor site was closed leaving the iliac crest donor site void unfilled.The midline incisions were closed in similar fashion. The procedure wasrepeated for the other animals using alternate levels L1–2 vs. L4–5.(Calcium polyphosphate graft placed at L1–2 and autologous bone atL4–5.)

The animals were housed in the intensive care unit in individual pens.Prophylactic antibiotics were administered for 24 hours. The sheep wereallowed to weight bear immediately. Postoperative analgesia wasadministered consisting of Bupernorphine 0.005 mg to kg q. 4–6 hours forpain. The animals were killed after six months by barbiturate overdose.The lumbar spine motion segments and iliac crests were harvested andcleaned of all soft tissues.

MANUAL PALPATION

At the time of harvest, the lumbar spines were manually palpated at thelevel of the fused motion segment, compared to the levels of theadjacent motion segments proximal and distal. This simulated fusionexploration and palpation in humans is considered the gold standard fordistinguishing nonunions and solid fusions. These motion segments weregraded as solid or not solid. Only levels grades as solid wereconsidered to be fused.

RADIOGRAPHIC ANALYSIS

Posterior/anterior radiographs were made and multiplane CT scans werethen performed of all motion segments. These radiographs were thenreviewed and the fusions were graded as solid or not solid based on thepresence of continuous trabeculac within the intertransverse fusionmass.

BIOMECHANICAL TESTING

Nondestructive cyclic testing was performed with an 8 by 8 bionichydraulic material testing machine (materials testing systems,Minneapolis, Minn.) on four axis, (flexion, extension, right lateralbending and left lateral bending). A ramp made in the shape of atriangle wave of 0.1 hertz was applied ten times, data was taken duringthe last cycle. Testing was performed using a 4 point bending model,intervertebral displacement was measured by an extensometer mountedanteriorly across the disc space at the level of fusion. Additionally,lumbar motion segments from sheep of similar size, age and weight werecompared as a control group.

LIGHT MICROSCOPIC ANALYSIS

The harvested spine specimens and iliac crest were fixed in 10%formalin. They were cut in half longitudinally in the sagittal plane andsagittal sections were sections were prepared. Undecalcified sectionswere dehydrated, infiltrated and imbedded in technovit basedmethylmethacrylate. Using a water cooled diamond saw, sectionsapproximately 150–200 microns in thickness were prepared. These werehand ground to approximately a thickness of 320 microns using siliconcartridge paper immersed in water and stained using a modified McNeals(tetrachrome stain). Sections were submitted from back scatter electronmicroscopy. This technique was used to analyze the volume fraction ofsoft tissue, bone, implant and osteointegration (percentage of theperimeter length of implant covered by bone) and compare the relativeamounts of soft tissue and calcified matrix in the sections.

RESULTS

Mortality and Complications

All sheep tolerated the surgical procedure well, they were ambulatingand gaining weight postoperatively. No infections occurred. One animalwas euthanized at one week postoperatively due to uncontrollable painprobably from the iliac crest donor site. There was no neurologicaldeficit noted. One other animal dies six weeks after surgery by anunrelated accident. The pre-operative morbidity rate was 16% (two deathsout of twelve sheep).

Gross Inspection/Palpation/Radiographs

Manual palpation of the fused and adjacent unfused segments wereperformed in all animals at the time of harvest. The fusion massesappeared larger in the calcium polyphosphate bioceramic levels comparedto the autologous grafted segments. The average volume beingapproximately 72 cm³ vs. 43 cm³, that is difference of 29.6 cm³ which issignificant (P value 0.0145). A fibrous membrane appeared to encapsulatethe fusion masses more noticeable on the calcium polyphosphatebioceramic fused segments compared to the autologous grafted segments.There was no evidence of gross inflammation. One of the spines developeda nonunion at both the autologous bone grafted level and at the calciumpolyphosphate bioceramic grafted level. On direct inspection andpalpation, one other nonunion was noted at a calcium polyphosphatebioceramic level. All of the remaining seventeen motion segmentsappeared to be successfully fused.

Radiographs confirmed bony trabeculation crossing the fusion mass in allthe unions. CT scans demonstrated incorporation of the bioceramic matchsticks into the fusion mass. The ceramic material lying further awayfrom the bony surface of the lamina appeared to have more soft tissueinterposition and variable bony ingrowth. The CT scans also confirmedthe size of the fusion masses being larger in the bioceramic levels whencompared to autologous levels.

BIOMECHANICAL TESTING

The slopes of the force vs. displacement and the force vs. strain curveswere calculated for each of the spine fusion segments analyzed. Morevariation appeared to occur in the slope of the force vs. strain datareflecting probable variations in the connection of the extensometerused to measure strain. Good results were seen with the force vs.displacement data reflecting direct measurement of the load sitedisplacement in the MTF fixture during the spine testing. Comparing theupper (L1–2) and the lower (L4–5) fusion segments showed no statisticalsignificant difference. The slope data was also analyzed to determine ifthe autologous and bioceramic fusion segments were comparable. Again,there was no statistical significant difference between the two. Boththe autologous and bioceramic spines had higher slopes when comparedwith the unfused controlled segments in all bending modes tested. All ofthese variations were statistically significant (p, 0.05). One of theautologous and two of the bioceramic spinal segments appeared to benotiunions showing very low values for the slope of the force vs.displacement curve in all four bending modes. This reconfirmed thefindings on direct manual palpation.

Light Microscopy and Backscatter Electron Microscopy Dystrometry

A dense collagenenous connective tissue with vascular capsule wasencountered on the surface of the fusion masses using the calciumpolyphosphate bioceramic. There was no evidence of an inflammatoryresponse nor resorption of the ceramic. Tremendous woven bone andosteoid was seen permeating between the ceramic material. Furthermore,proteinaceous material was seen within the ceramic pores of the materialitself. The SEM backscatter studies confirmed ingrowth of woven boneinto the porous implant matrix. The average new bone seen was 35.47%.The degree of osteo integration was also calculated by this method anddetermined to be on average 14.47%.

The model used in this example is similar to the posterolateralintertransverse fusion model used in humans. Two separate incisions wereutilized avoiding the risk of contamination between the two levels anddiminishing the amount of soft tissue stripping that occurred.Furthermore, no internal fixation was utilized. The calciumpolyphosphate material graft was used on its own without osteo inductiveagents such as bone marrow, bone morphogenic proteins or electricalstimulation. In this regard, the results of this example are better thanone might expect when one considers the challenging environment imposedon the artificial graft material. It is known that when using ceramics,it is critical to have direct apposition of the material to the hostbone, that the host bone is viable and that the interface between theimplant and the artificial bone by stabilized avoiding macro motion. Asmentioned, this example did not use internal fixation and thereforerigid fixation was not accomplished and yet acceptable fusion levels didoccur. The calcium polyphosphate bioceramics is an osteo-conductiveagent and a scaffolding for bony ingrowth. The CT scan studies andhistology studies confirmed that more bony ingrowth occurred near thesurface between the implant and the underlying host lamina bone, whilemore soft tissue ingrowth was seen between the ceramic strips lyingfurther away from the host bone as described by Booker. When oneconsiders this challenging environment, the nonunion rate of three outof 20 segments fused is an acceptable range (compared to human clinicalstudies). It is of interest that two of the nonunions occurred in thesame animal at an autologous level and at the bioceramic level.

The histological results confirmed bony ingrowth between and into theartificial material. The backscatter electron studies confirm ingrowthto be an average of 35.47%, which is comparable to other studies. Thebiomechanical studies confirmed the strength of the fusion masses to becomparable between the artificial bone and the autologous bone levels.It is possible, though, that more remodeling occurred at the autologousfusion segment leveis compared to the calcium polyphosphate bioceramiclevels as no evidence of resorption of the ceramic was noted and theaverage size of the fusion mass appeared larger in the artificial bonelevel compared to the autologous level, a difference of approximately29.6 cm³. The ceramic has been noted to slowly resorb with time and itwould be of interest to assess this implant material over a longerperiod.

The calcium polyphosphate material is noted to be much harder than otherceramics currently available and felt to posses strength comparable toautologous bone. The advantage of the calcium phosphate material of theinvention is more likely to be noted when used as a structurallysupportive material in situations under compression such as anteriorspinal column reconstructions.

In conclusion, this example shows that a fusion mass can be successfullycreated with the calcium polyphosphate material of the invention as anosteo-conductive scaffold for new bone ingrowth. Furthermore, the fusionmasses are mechanically comparable to the autologous levels. Both theriographic and histolotic evidence of bony ingrowth occurred and arecomparable to other studies using artificial bone implants. No softtissue inflammatory reaction occurred.

1. A method of producing a porous calcium phosphate material; composing:forming a mixture of calcium ions and phosphate ions having a calcium tophosphorus ratio of between 0.1 and about 0.80; heating said mixture totemperature of about 5° C. to 150° C. below the melting point of themixture; and cooling the reaction mixture, such that a porous calciumphosphate material is produced.
 2. The method of claim 1, furthercomprising preheating said mixture to 400° C. to 760° C. for at least 1second.
 3. The method of claim 2, wherein said mixture is preheated to400° C. to 760° C. for at least 1 second two or more times.
 4. Themethod of claim 1, further comprising compressing said mixture to apressure of 10,000 psi.
 5. The method of claim 1, wherein said ratio ofcalcium to phosphate ions is about 0.40 to about 0.60.
 6. The method ofclaim 4, further comprising heating said mixture at 250° C. to 400° C.for at least thirty minutes.
 7. The method of claim 1, furthercomprising placing the mixture into a mold prior to heating and pressingthe mixture to a pressure of 100 psi to 20,000 psi for at least 1second.
 8. The method of claim 7, further comprising ultrasonicvibration bombardment of said mixture.
 9. The method of claim 1, furthercomprising adding an acid catalyst to said mixture.
 10. The method ofclaim 9, wherein said acid catalyst is an inorganic or organic acid. 11.The method of claim 1, wherein said calcium ions are from apatiticcalcium phosphates, non-apatitic calcium phosphates, calcium hydroxide,calcium oxide, calcium carbonate, calcium salts, calcium halide, calciummetal, or combinations thereof.
 12. The method of claim 1, wherein saidphosphate ions are from orthophosphoric acid, pyrophosphoric acids,condensed phosphates, phosphate of non-metal cations, metal phosphates,or combinations thereof.
 13. The method of claim 1, wherein said mixtureis heated by an electric furnace, laser radiation, microwave radiationor radio frequency heating.
 14. A method of producing a porous calciumphosphate material comprising: forming a mixture of calcium ions andphosphate ions, wherein the ratio of calcium ions to phosphorous ions isbetween 0.1 and about 0.80; adding a gas-generating material to saidmixture; heating said mixture to about 5° C. to 150° C. below themelting point of the mixture; and cooling said mixture such that asolid, porous calcium phosphate material, is produced.
 15. The method ofclaim 14, wherein said gas-generating material is a source of ammoniumions selected from the group consisting of ammonium carbonate, ammoniumbicarbonate, ammonium acetate, ammonium hydroxide, ammonium nitrates,ammonium sulfates, ammonium hydrogen phosphate, ammoniumdihydrogenphosphate, ammonium fluorophosphates, ammonium citrate,ammonium hydrogencitrate, ammonium hydrogen difluoride, ammoniumhydrogen oxalate hemihydrate, ammonium halides, ammonium salts, ammoniaanhydride, ammonia solutions, and combinations thereof.
 16. A method ofproducing a porous non-apatatic calcium phosphate material comprising:mixing a gas-generating material and a calcium phosphate ceramicprecursor, heating said mixture to below the sintering temperature togenerate a gas; and sintering the calcium phosphate ceramic precursorsto make solid ceramic materials, such that a porous non-apatitic calciumphosphate material is produced.
 17. The method of claim 16, wherein saidcalcium phosphate ceramic precursor is monocalcium phosphate hydrate(MCP), dicalcium phosphate hydrate (DCPD), dicalcium phosphate anhydrous(DCPA), octacalcium phosphate pentahydrate (OCP), tricalcium phosphate(TCP), alpha and beta form (hydroxyapatite), pentacalciumhydroxylphosphate (HAP), tetracalcium phosphate monoxide (TCPM), calciumpyrophosphate, calcium metaphospates, polycalcium metaphospates, orcombinations thereof.